Studies of Induction of Alpha-Synuclein Inclusion Pathology

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Material Information

Title:
Studies of Induction of Alpha-Synuclein Inclusion Pathology
Physical Description:
1 online resource (231 p.)
Language:
english
Creator:
Sacino, Amanda N
Publisher:
University of Florida
Place of Publication:
Gainesville, Fla.
Publication Date:

Thesis/Dissertation Information

Degree:
Doctorate ( Ph.D.)
Degree Grantor:
University of Florida
Degree Disciplines:
Medical Sciences, Neuroscience (IDP)
Committee Chair:
GOLDE,TODD ELIOT
Committee Co-Chair:
GIASSON,BENOIT IVAN
Committee Members:
LEWIS,JADA M
BORCHELT,DAVID R
MCFARLAND,NIKOLAUS R
MUZYCZKA,NICHOLAS

Subjects

Subjects / Keywords:
alpha-synuclein -- neurodegeneration -- prion
Neuroscience (IDP) -- Dissertations, Academic -- UF
Genre:
Medical Sciences thesis, Ph.D.
bibliography   ( marcgt )
theses   ( marcgt )
government publication (state, provincial, terriorial, dependent)   ( marcgt )
born-digital   ( sobekcm )
Electronic Thesis or Dissertation

Notes

Abstract:
Alpha-Syucleinopathies are neurodegenerative disorders characterized by the accumulation of intracellular amyloidogenic alpha-synuclein (alpha-S) inclusions. Alpha-S is predominantly loosely localized around presynaptic vesicles of CNS neurons, where it is believed to assist in vesicular transport of neurotransmitters. It is not yet certain how alpha-S is triggered to misfold into amyloid and aggregate, how the amyloidogenic aS is transported, and if this contributes to the onset and progression of disease. Identification of modulators of alpha-S pathology may help to elucidate its role in disease, as well as provide molecular targets for therapeutic intervention. The focus of this dissertation is to characterize models of the induction ofalpha-S pathology in order to study contributing factors, which may also lead to elucidating mechanisms of disease progression. One of the leading hypotheses about neurodegenerative-associated pathology is that induction and spread is via a prionoid mechanism, where the misfolded protein is transmitted intercellularly and serves as a template for the conformational conversion of soluble intracellular protein into amyloid. Post-mortem studies completed on PD patients have shown i) that there may be a pattern of spread of alpha-S pathology from the peripheral nervous system to the central nervous system, and ii) that alpha-S pathology may have transmitted to therapeutic naive fetal dopaminergic neuron grafts. In conjunction with recent cell culture and in vivo studies showing that the addition of exogenous alpha-S fibrils can lead to alpha-S pathology induction, a hypothesis was proposed that aS pathology, as seen in Parkinson's disease, is behaving in a prionoid manner. Using a cell culture model and in vivo mouse models ofalpha-S pathology, we have extended these studies demonstrating that i) missense mutations of alpha-S differ in their pathology induction properties, ii) that there are significant barriers to widespread induction of alpha-S pathology in vivo, iii) that additional factors, such as neuroflammation and disruption of proteostasis, may play a role in induction and spread, and iv) that caution should be used when defining alpha-S pathology via its main antibody marker, pSer129. Collectively, these studies serve as a foundation for future mechanistic work on alpha-S pathogenesis.
General Note:
In the series University of Florida Digital Collections.
General Note:
Includes vita.
Bibliography:
Includes bibliographical references.
Source of Description:
Description based on online resource; title from PDF title page.
Source of Description:
This bibliographic record is available under the Creative Commons CC0 public domain dedication. The University of Florida Libraries, as creator of this bibliographic record, has waived all rights to it worldwide under copyright law, including all related and neighboring rights, to the extent allowed by law.
Statement of Responsibility:
by Amanda N Sacino.
Thesis:
Thesis (Ph.D.)--University of Florida, 2014.
Local:
Adviser: GOLDE,TODD ELIOT.
Local:
Co-adviser: GIASSON,BENOIT IVAN.
Electronic Access:
RESTRICTED TO UF STUDENTS, STAFF, FACULTY, AND ON-CAMPUS USE UNTIL 2016-05-31

Record Information

Source Institution:
UFRGP
Rights Management:
Applicable rights reserved.
Classification:
lcc - LD1780 2014
System ID:
UFE0046504:00001